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Influence of metformin on energy metabolism of mice exposed to cigarette smoke.

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Vanessa de Cássia Martins Pires
Total Authors: 1
Document type: Master's Dissertation
Press: Botucatu. 2018-05-07.
Institution: Universidade Estadual Paulista (Unesp). Faculdade de Medicina. Botucatu
Defense date:
Advisor: Paula Schmidt Azevedo Gaiolla

Introduction: Exposure to cigarette smoke (ECS) not only increases the risk for cardiovascular disease but also directly damages the myocardium. Experimental and clinical studies show that ECS is associated with hypertrophy and myocardial dysfunction, regardless of vascular factors. Little is known about the mechanisms involved with myocardial injury induced by ECS. Among these mechanisms are the changes in energy metabolism. In a normal heart, 60 to 90% of the adenosine triphosphate (ATP) comes from the fatty acid oxidation (FA). In pathological conditions, there are alterations in the use of substrates, in mitochondrial biogenesis and finally in the production of ATP, which may compromise morphology and cardiac function. Studies show that smoking can lead to insulin resistance, which in turn can compromise cardiac bioenergetics. However, it is not known whether there is impairment of the cardiac energy metabolism associated with the insulin resistance induced by the ECS. Additionally, in experimental studies, metformin has been shown to be effective in attenuating cardiac remodeling, mainly by acting on energy metabolism. Objectives: The objective of this study was to evaluate the role of metformin in cardiac remodeling induced by cigarette smoke through cardiac morphofunctional evaluation, oxidative stress, energy metabolism, and expression of proteins that participate in glucose metabolism. Material and Methods: Sixty animals were allocated to four groups of 15 animals each: ECS group (n = 15), composed of animals exposed to cigarette smoke; ECS-MET (n = 15) consisting of animals exposed to cigarette smoke and with ingestion of metformin diluted in water; group C (n = 15) and MET group (n = 15) who received metformin diluted in water. After 2 months the animals were submitted to: a) biochemical study to evaluate the exposure to cigarette; b) echocardiographic study for morphofunctional evaluation; c) measurement of caudal blood pressure; d) histological study using immunofluorescence to evaluate hypertrophy, angiogenesis and GLUt-4 translocation; e) Western Blot for evaluation of the expression of proteins involved with insulin resistance and glucose metabolism; f) spectrophotometric evaluation to evaluate the activity of energy metabolism enzymes and the amount of cardiac glycogen. RESULTS: ECS animals had left atrial enlargement (AE), left ventricular diameter (LVDD), left ventricular mass (LVMI), relative posterior wall thickness (ERP) followed by diastolic dysfunction. Metformin attenuated the size of AE, ERP, diastolic dysfunction in ECS animals. Regarding the potentially involved mechanisms, it was observed that the ECS increased the formation of lipid hydroperoxide, but the association with metformin and smoke increased even more. However, metformin, independently of the ECS increased the activity of the antioxidant enzymes catalase and superoxide dismutase. Regarding energetic metabolism, it was observed that smoking independently of metformin reduced the activity of complex I and ATP synthase. On the other hand, metformin increased the activity of complex I, II and ATP synthase, independently of the ECS. There was no interaction between smoking and metformin for energy metabolism. Regarding the expression of glucose metabolism proteins, it was observed that phosphorylated AKT / total AKT and membrane GLUT-4 decreased with smoke and were attenuated by metformin. Conclusion: Metformin attenuates the damage generated by the ECS, probably not by reducing oxidative stress. There is a possibility that ECS may induce altered glucose metabolism, which in cardiac tissue has been attenuated by metformin, perhaps by increasing the phosphorylation of AKT and increasing GLUT-4 in the membrane. (AU)

FAPESP's process: 16/14547-0 - Influence of metformin in cardiac energy metabolism of rats exposed to cigarrette smoke
Grantee:Vanessa de Cássia Martins Pires Ferreira
Support Opportunities: Scholarships in Brazil - Master